Abstract

Aim

BRAFi (D) and MEKi (T) each demonstrated superior progression-free survival (PFS) vs. chemotherapy in pts with BRAF V600E/K mutation-positive metastatic melanoma (MM). However, the emergence of disease resistance and development of cutaneous squamous cell carcinoma (cuSCC) are associated with BRAF inhibition. Simultaneous inhibition of BRAF and MEK mitigated these effects as shown in the Phase I/II study of D+T combination therapy vs. D monotherapy (NCT01072175) and the Phase III study of D+T combination therapy vs. D monotherapy (NCT01584648), with an improvement in overall response rate (ORR), PFS and reduced frequency of cuSCC. This Phase III study (NCT01597908) was conducted to establish superiority of D+T combination over V with respect to overall survival (OS) in pts with BRAF V600E/K mutation-positive MM.

Methods

Pts were randomised 1:1 to receive D (150 mg twice daily [BID]) and T (2 mg once daily) vs. V monotherapy (960 mg BID) as first-line therapy. Eligible pts were ≥ 18 years old and had an ECOG performance status ≤ 1, with histologically confirmed, unresectable stage IIIC or IV, BRAF V600E/K mutation-positive MM. The primary endpoint was OS; secondary endpoints were PFS, ORR, duration of response, and safety. Crossover was prohibited. A pre-specified interim OS analysis was performed when 77% (222/288) of the total number of expected deaths, required for the protocol-specified final analysis, were observed; the study could be stopped for efficacy if the one-sided P value was < 0.0107.

Results

From June 2012 to Oct 2013, 704 pts were randomised (352 to each arm). IDMC recommended stopping study based on an interim analysis which demonstrated an OS benefit that crossed the pre-specified efficacy stopping boundary for D+T combination. Rates of adverse events were generally similar for both arms and consistent with data from previous trials. Full efficacy and safety results will be presented at the meeting.